In recent years there has been an increased recognition of the seriousness of uncontrolled hypertension. The disease is particularly dangerous because it is, in most instances silent, and can result in stroke or heart attack if left untreated for a period of time. Because the etiology of most cases of hypertension is not understood, the search for effective anti-hypertensive agents has been largely empirical. This approach has led to a number of useful drugs with widely varied mechanisms of action.
One such drug has been recently introduced to the market and represents the first in a new chemical class of antihypertensive agents, the hydrochloride salt of 1-(4-amino-6,7-dimethoxy-2-quinazolinyl-4-(2-furanylcarbonyl)piperazine, which has the generic name prazosin hydrochloride. Prazosin hydrochloride is represented by the formula: ##STR1## This drug however, as reported in The Lancet, May 10, 1975, at page 1095, exhibits significant toxicity and can cause a profound fall in blood pressure. Sudden collapse with loss of consciousness for periods ranging from a few minutes to one hour following use of this drug have been reported. (The Lancet and British Medical Journal, June 28, 1975, pages 727, 728. See also The Physicians Desk Reference, 33rd Edition, p. 1343, Medical Economics Co. (1979). Furthermore, the compound is relatively insoluble in water and is not administered parenterally.
A related compound, the hydrochloride salt of 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-tetrahydrofuroyl) piperazine has also been reported to be useful as an antihypertensive agent, is less toxic than prazosin hydrochloride, is highly soluble in water and can be administered parenterally as well as orally. See U.S. Pat. No. 4,026,894 (The compound is named 2[4(tetrahydro-2-furoyl)-piperazino]-4-amino-6,7-dimethoxyquinazoline therein). The newly reported compound, hereinafter referred to as the compound of Formula II, is represented by the formula: ##STR2##
The compound of Formula II, because of its greatly enhanced solubility, can be administered parenterally, whereas prazosin hydrochloride is only available in tablet form for oral administration. Thus prazosin cannot be used in emergency situations which require intravenous administration of an effective antihypertensive agent to rapidly lower blood pressure in a patient suffering from a hypertensive crisis.
It has now surprisingly been found that the dihydrate of the compound of Formula II has numerous advantages over the anhydrous compound. The dihydrate, while less water soluble than the compound of Formula II, is far more stable in solution that the compound of Formula II and thus is considerably more suitable for parenteral administration. Furthermore, the compound of this invention is more stable when stored in bulk prior to tableting than the compound of Formula II which is hygroscopic and thus picks up moisture upon storage. The lessened tendency toward hygroscopicity of the compound of this invention is very important because the accuracy of weighing out bulk compound for tableting purposes would be affected if the compound's weight is partially attributable to water of hydration. Thus, constant assaying would be required to ensure that the proper amount of active drug is provided. Tableting accuracy is particularly critical since the drug is effective at such small dosages.
While the compound of Formula II is highly useful as an anti-hypertensive agent, the compound of this invention has the added advantages of ease of manufacture, stability in solution, lends itself to more accurate tableting procedures and is far less hydroscopic which results in greater physical stability and greater ease of assaying drug content.